A super-relaxed myosin state to offset hypertrophic cardiomyopathy

At its most basic level, the proper functioning of the heart depends upon the intricate interaction of proteins that trigger, maintain, and control the muscular contractions and relaxations of this vital organ. Disruption of those interactions can cause serious pathologies such as hypertrophic cardiomyopathy (HCM). Such disruptions can originate with mutations in the primary motor protein involved in heart contraction, ß-cardiac myosin, which can alter the rate of ATP hydrolysis and have been hypothesized to destabilize its super-relaxed state (SRX). Researchers investigated the stabilizing action of mavacamten, a cardiac drug currently in phase 3 clinical trials, on the ß-cardiac myosin super-relaxed state and its possible therapeutic effects on HCM. Their work, which included electron microscopy and low-angle x-ray diffraction at the U.S. Department of Energy’s Advanced Photon Source (APS), was published in Proceedings of the National Academies of Sciences of the United States of America.

Previous work had hinted that a folded state of the myosin protein, seen both in purified form and in isolated filaments and known as the interacting-heads motif or IHM, could be analogous to the SRX state, although this has not yet been demonstrated experimentally. It has been proposed that mutations causing HCM disrupt this state, resulting in a higher percentage of myosin heads being available for interaction with actin and leading to the hypercontractility of cardiac tissue seen in HCM. These investigators, from  MyoKardia, Inc., the Stanford University School of Medicine, the Illinois Institute of Technology, Exemplar Genetics, the Harvard Medical School, and the University of California, San Francisco, first studied this possibility using three separate purified ß-cardiac myosin constructs (25-heptad heavy meromysin [HMM], two-heptad HMM, and short S1), finding that a fraction of their basal ATPase rates were within the range of 0.002-0.004 s-1 which defines the SRX state.

>Read more on the Advanced Photon Source at Argonne National Laboratory

Image: The figure (a) shows a diffraction pattern from untreated muscle compared to treated muscle on the right. Intensification of the x-ray reflections from the treated muscle indicate a highly ordered “super-relaxed” state of myosin motors. Figure (b) shows the myosin heads in the compact “interacting head motif” which the heads adopt in the super-relaxed state allowing them to be packed closely and tightly on the surface of muscle thick filaments.